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Park JM, Kim J, Lee YJ, Bae SU, Lee HW. Inflammatory bowel disease-associated intestinal fibrosis. J Pathol Transl Med 2023; 57:60-66. [PMID: 36623814 PMCID: PMC9846010 DOI: 10.4132/jptm.2022.11.02] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 01/11/2023] Open
Abstract
Fibrosis is characterized by a proliferation of fibroblasts and excessive extracellular matrix following chronic inflammation, and this replacement of organ tissue with fibrotic tissue causes a loss of function. Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract, and intestinal fibrosis is common in IBD patients, resulting in several complications that require surgery, such as a stricture or penetration. This review describes the pathogenesis and various factors involved in intestinal fibrosis in IBD, including cytokines, growth factors, epithelial-mesenchymal and endothelial-mesenchymal transitions, and gut microbiota. Furthermore, histopathologic findings and scoring systems used for stenosis in IBD are discussed, and differences in the fibrosis patterns of ulcerative colitis and Crohn's disease are compared. Biomarkers and therapeutic agents targeting intestinal fibrosis are briefly mentioned at the end.
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Affiliation(s)
- Ji Min Park
- Department of Pathology, Keimyung University School of Medicine, Daegu,
Korea
| | - Jeongseok Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu,
Korea
| | - Yoo Jin Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu,
Korea
| | - Sung Uk Bae
- Division of Colorectal Surgery, Department of Surgery, Keimyung University School of Medicine, Daegu,
Korea
| | - Hye Won Lee
- Department of Pathology, Keimyung University School of Medicine, Daegu,
Korea
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The role of NOD2 in intestinal immune response and microbiota modulation: A therapeutic target in inflammatory bowel disease. Int Immunopharmacol 2022; 113:109466. [DOI: 10.1016/j.intimp.2022.109466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 10/11/2022] [Accepted: 10/24/2022] [Indexed: 11/25/2022]
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Wang D. NOD1 and NOD2 Are Potential Therapeutic Targets for Cancer Immunotherapy. COMPUTATIONAL INTELLIGENCE AND NEUROSCIENCE 2022; 2022:2271788. [PMID: 36262606 PMCID: PMC9576356 DOI: 10.1155/2022/2271788] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 02/05/2023]
Abstract
The nucleotide oligomerization domain (NOD)-like receptors (NLRs) are a group of intracellular proteins that are essential for controlling the host's innate immune response. The cytosolic nucleotide binding oligomerization domains 1 and 2 receptors (NOD1 and NOD2) are the most widely investigated NLRs. As pattern recognition receptors (PRRs), NOD1 and NOD2 may recognize and bind endogenous damage associated molecular patterns (DAMPs) and external pathogenic associated molecular patterns (PAMPs), directing the activation of inflammatory caspases through engaging the adaptor protein RIP2, which further activates the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, thereby mediating host innate immunity and regulating the adaptive immunity. Previous research has identified NOD1 and NOD2 as key players in inflammatory disease and host-microbial defense. Despite numerous studies claiming that NOD1 and NOD2 are linked to tumorigenesis and tumor development, it is still unclear whether NOD1 and NOD2 act as cancer's friends or foes. In this review, we focus on concluding the current research progress on the role of NOD1 and NOD2 in a variety of cancers and discussing the potential reasons for the contradicting role of NOD1 and NOD2 in cancers. This review may help better understand the role of NOD1 and NOD2 in cancer and shed light on NOD1 and NOD2 as potential therapeutic targets for tumor immunotherapy.
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Affiliation(s)
- Dongjie Wang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan 450003, China
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4
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The role of IL-10 in microbiome-associated immune modulation and disease tolerance. Cytokine 2015; 75:291-301. [DOI: 10.1016/j.cyto.2014.11.027] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Revised: 11/20/2014] [Accepted: 11/21/2014] [Indexed: 02/06/2023]
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Boukercha A, Mesbah-Amroun H, Bouzidi A, Saoula H, Nakkemouche M, Roy M, Hugot JP, Touil-Boukoffa C. NOD2/ CARD15 gene mutations in North Algerian patients with inflammatory bowel disease. World J Gastroenterol 2015; 21:7786-7794. [PMID: 26167078 PMCID: PMC4491965 DOI: 10.3748/wjg.v21.i25.7786] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 04/23/2015] [Accepted: 05/07/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyse allelic frequency of NOD2 gene variants and to assess their correlation with inflammatory bowel disease (IBD) in Algeria.
METHODS: We studied 132 unrelated patients diagnosed with IBD, 86 with Crohn’s disease (CD) and 46 with ulcerative colitis (UC). Data was prospectively collected between January 2011 and December 2013. The demographic and clinical characteristics were recorded for all the patients. A group of 114 healthy unrelated individuals were selected as controls. All groups studied originated from different regions of North Algeria and confirmed the Algerian origin of their parents and grandparents. Informed and written consent was obtained from each of the participants. All individuals were genotyped for the three CD-associated NOD2 variants (p.Arg702Trp, p.Gly908Arg and p.Leu1007fsinsC mutations) using the polymerase chain reaction-restriction fragment length polymorphism method. Allele and genotype frequencies in patients and control subjects were compared by χ2 test and Fisher’s exact test where appropriate. Odds ratios (OR) and 95% confidence intervals (95%CI) were also estimated. Association analyses were performed to study the influence of these variants on IBD and on clinical phenotypes.
RESULTS: The p.Arg702Trp mutation showed the highest frequency in CD patients (8%) compared to UC patients (2%) (P = 0.09, OR = 3.67, 95%CI: 0.48-4.87) and controls (5%) (P = 0.4, OR = 1.47, 95%CI: 0.65-3.31). In CD patients allelic frequencies of p.Gly908Arg and p.Leu1007fsinsC variants compared to HC were 3% vs 2% (P = 0.5, OR = 1.67, 95%CI: 0.44-6.34); 2% vs 1% (P = 0.4 OR = 2.69 95%CI: 0.48-14.87 respectively). In UC patients, allelic frequencies of p.Gly908Arg and p.Leu1007fsinsC variants compared to HC were 1% vs 2% (P = 1, OR = 1.62, 95%CI: 0.17-4.74) and 2% vs 1% (P = 0.32, OR = 0.39, 95%CI: 0.05-2.87). The total frequency of the mutated NOD2 chromosomes was higher in CD (13%), than in HC (8%) and UC (5%). In addition, NOD2 variants were linked to a particular clinical sub-phenotype in CD in this Algerian cohort. As expected, the three NOD2 variants showed a significant association with CD but did not reach statistical significance, despite the fact that the allele frequency of NOD2 variants was in the range found in most of the European populations. This might be due to the non-exposure of the NOD2 carriers to environmental factors, required for the expression of the disease.
CONCLUSION: Further analyses are necessary to study genetic and environmental factors in IBD in the Algerian population, using larger patient groups.
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Abstract
: Restorative proctocolectomy with ileal pouch-anal anastomosis is commonly used in the management of ulcerative colitis. Inflammation of the ileal pouch reservoir, or pouchitis, is a common complication of ileal pouch-anal anastomosis that is incompletely understood. Risk factors including nonsmoker status and primary sclerosing cholangitis have been linked with pouchitis development, but the etiopathogenesis of pouchitis remains poorly defined. Pouchitis is more commonly a complication of ileal pouch-anal anastomosis performed in patients with ulcerative colitis, and similar to ulcerative colitis, chronic pouchitis is associated with extraintestinal manifestations and other diseases of immune origin, suggesting overlap in the disease pathogenesis. It is becoming apparent that pouchitis encompasses clinically distinct subtypes based on the response or lack of response to antibiotic therapy. There is also emerging evidence of the role of autoimmunity in a subgroup of patients with pouchitis, including patients with concurrent primary sclerosing cholangitis, seropositivity for immunoglobulin G4, or infiltration of immunoglobulin G4-expressing plasma cells in the pouch mucosa. The identification of underlying autoimmunity may have important clinical implications in the diagnosis, subclassification, and management of pouchitis.
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Ahmed FE. Role of genes, the environment and their interactions in the etiology of inflammatory bowel diseases. Expert Rev Mol Diagn 2014; 6:345-63. [PMID: 16706738 DOI: 10.1586/14737159.6.3.345] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Few of the studied genes demonstrate association with inflammatory bowel disease (IBD). Three mutations in the nucleotide-binding oligomerization domain 2 gene have consistently shown to be independent risk factors for Crohn's disease, but none of the alleles exhibited high sensitivity or specificity for IBD. Linkage analysis implicated several loci on various chromosomes, and epistasis has been demonstrated. The etiopathogenesis of IBD remains unknown, and environmental contribution to their pathogenesis is evident from genetic studies that demonstrated incomplete monozygotic twins concordandance rate for both Crohn's and ulcerative colitis. Smoking has shown an opposite effect on disease phenotype, with an adverse effect on disease course for Crohn's disease, but a slight beneficial effect in ulcerative colitis. The contribution of infectious agents to susceptibility to IBD appears to be strong. However, the role of nutrition on the etiology and therapy of IBD is not clear. Inconsistencies in environmental risk factors could be due to gene-environment interactions, making it essential to study the role of genetics and environmental contribution to the etiopathology of IBD. Transgenic or knockout mice, such as interleukin-10(-/-), T-cell receptor alpha(-/-), Galphai(2) (-/-) and N-cadherin(-/-), develop colitis-like inflammation similar to humans. Therefore, animal models must be further studied to explore mechanistic interactions.
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Affiliation(s)
- Farid E Ahmed
- The Brody School of Medicine at East Carolina University, Department of Radiation Oncology, Leo W Jenkins Cancer Center, Greenville, NC 27858, USA.
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Speca S, Giusti I, Rieder F, Latella G. Cellular and molecular mechanisms of intestinal fibrosis. World J Gastroenterol 2012; 18:3635-61. [PMID: 22851857 PMCID: PMC3406417 DOI: 10.3748/wjg.v18.i28.3635] [Citation(s) in RCA: 197] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2011] [Revised: 03/26/2012] [Accepted: 04/09/2012] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelial- and endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic process, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.
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Kutikhin AG. Role of NOD1/CARD4 and NOD2/CARD15 gene polymorphisms in cancer etiology. Hum Immunol 2011; 72:955-68. [PMID: 21745515 DOI: 10.1016/j.humimm.2011.06.003] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2011] [Revised: 05/30/2011] [Accepted: 06/08/2011] [Indexed: 02/08/2023]
Abstract
NOD1/CARD4 and NOD2/CARD15 are members of Nod-like receptor family. They are located in cytosol, bind bacterial and viral ligands and play a key role in realization of innate and adaptive immune response, apoptosis, autophagy, and reactive oxygen species generation. Polymorphisms in NOD1/CARD4 and NOD2/CARD15 genes may shift balance between pro- and anti-inflammatory cytokines, modulating the risk of infection, chronic inflammation and cancer. NOD1/CARD4 and NOD2/CARD15 gene polymorphisms may be associated with altered risk of gastric, colorectal, breast, ovarian, prostate, testicular, lung, laryngeal, liver, gallbladder, biliary tract, pancreatic, small bowel, kidney, urinary bladder cancer, skin cancer, nonthyroid endocrine tumors, lymphoma and leukemia. The short list of such polymorphisms perspective for oncogenomic investigations may include rs2006847, rs2066845, rs2066844, rs2066842, ND(1)+32656, rs2075820 whereas rs104895493, rs104895476, rs104895475, rs104895474, rs104895473, rs104895472, rs104895462, rs104895461, rs104895460, rs104895438, rs5743291, rs5743260, rs2076756, rs2066843, Pro371Thr, Ala794Pro, Gln908His, rs72551113, rs72551107, rs6958571, rs2907749, rs2907748, rs2075822, rs2075819, rs2075818 may be added to the extended list. Reasons of discrepancies between different studies include confounding host genetic, bacterial, or environmental factors modulating penetrance of variant allele and affecting risk of condition increasing cancer risk, different bacterial impact in aetiology of such conditions, differences in sample size, clinicopathological characteristics, diagnostics, stratification, genotyping methods, and chance.
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Affiliation(s)
- Anton G Kutikhin
- Department of Epidemiology, Kemerovo State Medical Academy, Kemerovo, Russia.
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Clustering of (auto)immune diseases with early-onset and complicated inflammatory bowel disease. Eur J Pediatr 2009; 168:575-83. [PMID: 18670786 DOI: 10.1007/s00431-008-0798-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2008] [Revised: 06/05/2008] [Accepted: 07/02/2008] [Indexed: 01/14/2023]
Abstract
Studies in adult inflammatory bowel disease (IBD) patients have highlighted associations with genetic and serologic markers and suggest an association with disease location, behaviour and natural history. Data on patients with Crohn's disease (CD, n=80), ulcerative colitis (UC, n=15) and indeterminate colitis (n=4) were collected. All individuals were analysed for CARD15 R702W, G908R and L1007fs for toll-like receptor 4 (TLR4) Asp299Gly and for anti-Saccharomyces cerevisiae antibodies (ASCA) and atypical perinuclear antineutrophil cytoplasmatic antibodies (pANCA). After a mean of 10.7 years of follow up, the disease behaviour changed in 45% of CD patients, in contrast to disease location, where only 12.5% had a change (p<0.001). The younger the age at diagnosis, the more patients presented with colonic disease (p=0.021). Also, more TLR4 Asp299 Gly variants were found when the age at onset was younger (p=0.018). A large number of concomitant diseases were observed. There was no difference in the prevalence of TLR4 variants nor ASCA or pANCA between the patients with or without concomitant diseases. Patients who progressed more often needed surgery as compared to patients who remained free of stenosing or fistulising disease (27/32 or 84% versus 3/35 or 8.6%, respectively, p<0.0001) and more often had concomitant immune-mediated diseases and a trend for more seroreactivity towards ASCA.
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Juyal G, Amre D, Midha V, Sood A, Seidman E, Thelma BK. Evidence of allelic heterogeneity for associations between the NOD2/CARD15 gene and ulcerative colitis among North Indians. Aliment Pharmacol Ther 2007; 26:1325-32. [PMID: 17892524 DOI: 10.1111/j.1365-2036.2007.03524.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Three common disease susceptibility variants in the NOD2 gene are associated with inflammatory bowel disease in Caucasians, but not in Asians. Aim To screen for NOD2 variants and examine susceptibility for inflammatory bowel disease in North Indians. METHODS A case-control study was carried out in Punjab, India. Confirmed cases of ulcerative colitis and Crohn's disease and healthy controls matched for age (+/-10 years) and ethnicity were studied. Besides genotyping the three disease susceptibility variants (SNP8, SNP12 and SNP13), all 12 exons were resequenced to determine other potential single nucleotide polymorphisms. RESULTS Two hundred and ninety-eight ulcerative colitis, 25 Crohn's disease and 262 controls were investigated. Median age (range) at diagnosis was 39 (7-78) years for ulcerative colitis and 40 (32-58) years for Crohn's disease. All three disease susceptibility variants were either monomorphic or rare in the population. Sequencing (n = 30) revealed two single nucleotide polymorphisms: SNP5 (268 Pro/Ser) and rs2067085 (178 Ser/Ser). The frequency of SNP5 was higher among ulcerative colitis (17% vs. 12% in controls, P = 0.016) and Crohn's disease cases (20% vs. 12%, P = 0.28). SNP5 carriers had elevated risks for ulcerative colitis (OR = 1.72, 95% CI = 1.17-2.52, P = 0.005). CONCLUSIONS The absence of known inflammatory bowel disease susceptibility variants and potential associations between SNP5 and ulcerative colitis in North Indians suggests the presence of allelic heterogeneity for ulcerative colitis susceptibility.
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Affiliation(s)
- G Juyal
- Department of Genetics, University of Delhi, South Campus, New Delhi, India
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van der Linde K, Boor PPC, Houwing-Duistermaat JJ, Crusius BJA, Wilson PJH, Kuipers EJ, de Rooij FWM. CARD15 mutations in Dutch familial and sporadic inflammatory bowel disease and an overview of European studies. Eur J Gastroenterol Hepatol 2007; 19:449-59. [PMID: 17489054 DOI: 10.1097/01.meg.0000236887.44214.6a] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES The single nucleotide variations R702W, G908R and L1007fs in the CARD15 gene have been found to be independently associated with Crohn's disease. The aim of this study was to evaluate the prevalence of these gene variations in Dutch multiple inflammatory bowel disease-affected families, in sporadic inflammatory bowel disease patients and in healthy controls. METHODS Dutch Caucasians from multiple inflammatory bowel disease-affected families were recruited, including 78 probands with Crohn's disease, 34 probands with ulcerative colitis and 71 inflammatory bowel disease-affected and 100 non-affected family members. In addition, 45 sporadic inflammatory bowel disease patients (36 Crohn's disease and nine ulcerative colitis), and 77 unrelated healthy controls were included. Genomic DNA was isolated to determine CARD15 R702W, G908R and L1007fs. For these mutations, we evaluated disease susceptibility and correlation with inflammatory bowel disease phenotypes. RESULTS In all included unrelated inflammatory bowel disease-affected probands, the R702W, G908R and L1007fs allele frequencies were 8.8, 6.1 and 11.0%, respectively, for Crohn's disease, and 4.7, 0 and 2.3% for ulcerative colitis. In controls, the allele frequencies were 5.9, 0.7 and 1.9%, respectively. G908R and L1007fs were associated with Crohn's disease (P=0.006 and 0.001, respectively). Compound heterozygotes for any of the three mutations were 11 (9.2%) in Crohn's disease patients, but none in ulcerative colitis patients nor controls. Carriage of CARD15 mutations was not associated with familial disease (P>or=0.38). Inflammatory bowel disease-affected family members of Crohn's disease probands carrying L1007fs, however, were carriers significantly more often than expected (P<0.001). In Crohn's disease patients, a significant trend was found between carriage of at least one CARD15 mutation and between carriage of L1007fs and behaviour of disease, including more carriers with stricturing and even more with penetrating disease (P=0.006 and 0.017, respectively). CONCLUSION In the Dutch population, CARD15 G908R and L1007fs are associated with Crohn's disease. Although no difference was found between sporadic and familial cases, in L1007fs-positive multiple affected families the inflammatory bowel disease-affected relatives are more likely than expected to carry this mutation. In Crohn's disease, carriage of at least one CARD15 mutation is associated with a more complicated disease behaviour.
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Affiliation(s)
- Klaas van der Linde
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
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Brant SR, Wang MH, Rawsthorne P, Sargent M, Datta LW, Nouvet F, Shugart YY, Bernstein CN. A population-based case-control study of CARD15 and other risk factors in Crohn's disease and ulcerative colitis. Am J Gastroenterol 2007; 102:313-23. [PMID: 17100976 DOI: 10.1111/j.1572-0241.2006.00926.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Multiple established Crohn's disease (CD) and ulcerative colitis (UC) risk factors including family history, tobacco use, Jewish ethnicity, urban residency, and CARD15/NOD2 mutations have been evaluated singly and in hospital-based observational studies. The goal of this study was to assess the relative contributions of all these risk factors jointly in a nonreferral, population-based cohort derived from a population epidemiologic database. METHODS CD (N = 232) and UC (N = 121) subjects were ascertained from our population-based IBD Registry derived from Manitoba Health, the single provincial insurer. Healthy controls (HC) (N = 336) were recruited via a 10:1 mailing matched for age, sex, and postal code. Ethnicity, tobacco use, family history, residency, and CARD15/NOD2 genotype status were determined. RESULTS In both univariate analyses and analyses adjusted for all risk factors, CD was influenced independently by CARD15/NOD2 heterozygote and homozygote/compound-heterozygote status (adjusted odds ratios [OR] 3.7 and 40.0, respectively), Jewish ethnicity (OR 18.5), CD family history (OR 6.2), and smoking (OR 3.0 current and 1.7 ex-smoker, respectively). Penetrance for homozygote/compound-heterozygotes was 4.9%, heterozygotes 0.54%, and wild types 0.184%. Population attributable risk for CARD15 was 26.7% and current tobacco use was 46.8%. A tobacco-CARD15 interaction was not observed. UC was influenced by Jewish ethnicity (OR 37.1), and by family history (OR 2.6), ex-smoker status (OR 1.9), and CARD15/NOD2 heterozygote or homozygote/compound-heterozygote status (OR 1.9 and 6.4, respectively) in adjusted analyses only. CONCLUSIONS CARD15/NOD2, family history, smoking, and Jewish ethnicity are independent risk factors for CD. Examination of these risk factors together in a single population-based cohort has provided initial data for population epidemiological characterization and genetic counseling uses.
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Affiliation(s)
- Steven R Brant
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
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Oostenbrug LE, Nolte IM, Oosterom E, van der Steege G, te Meerman GJ, van Dullemen HM, Drenth JPH, de Jong DJ, van der Linde K, Jansen PLM, Kleibeuker JH. CARD15 in inflammatory bowel disease and Crohn's disease phenotypes: an association study and pooled analysis. Dig Liver Dis 2006; 38:834-45. [PMID: 16920047 DOI: 10.1016/j.dld.2006.06.042] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2006] [Revised: 06/22/2006] [Accepted: 06/27/2006] [Indexed: 12/11/2022]
Abstract
BACKGROUND Three major polymorphisms of the Caspase-Activation Recruitment Domain containing protein 15 gene have been described to be associated with Crohn's disease. Genotype-phenotype studies reported in literature provide conflicting data on disease localisation and behaviour. We investigated the relation of Caspase-Activation Recruitment Domain containing protein 15 with inflammatory bowel disease and Crohn's disease phenotypic characteristics in a large Dutch cohort and performed a pooled analysis on inflammatory bowel disease patients and Crohn's disease phenotypic characteristics reported in association studies. METHODS We genotyped 781 cases and 315 controls for the R702W, G908R and 1007fsinsC variants and for six microsatellite markers in and close to Caspase-Activation Recruitment Domain containing protein 15. In the pooled analysis data of 7201 inflammatory bowel disease patients and 3720 controls from 20 studies were included. RESULTS Association was found for Crohn's disease with R702W and 1007fsinsC, including several disease characteristics, and not for ulcerative colitis. In the pooled analysis all three common Caspase-Activation Recruitment Domain containing protein 15 variants showed strong association with Crohn's disease (p<0.00001; odds ratio varying from 3.0 for single heterozygotes to 14.7 for compound heterozygotes) and not with ulcerative colitis. Phenotype analysis showed association with small bowel involvement, stricturing and penetrating disease. CONCLUSION Caspase-Activation Recruitment Domain containing protein 15 is associated with Crohn's disease and not with ulcerative colitis. All three common Crohn's disease-associated variants are associated with small bowel involvement, the G908R and 1007fsinsC alleles also being associated with a complicated disease course.
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Affiliation(s)
- L E Oostenbrug
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands.
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De Jager PL, Graham R, Farwell L, Sawcer S, Richardson A, Behrens TW, Compston A, Hafler DA, Kere J, Vyse TJ, Rioux JD. The role of inflammatory bowel disease susceptibility loci in multiple sclerosis and systemic lupus erythematosus. Genes Immun 2006; 7:327-34. [PMID: 16642031 DOI: 10.1038/sj.gene.6364303] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
To date, three loci have been validated to confer susceptibility to inflammatory bowel disease (IBD): the CARD15/NOD2 gene, the discs large homolog 5 gene (DLG5), and the IBD5 locus on 5q31 (IBD5). We have explored the possibility that these loci may also be associated with susceptibility to two other chronic inflammatory diseases, multiple sclerosis (MS) and systemic lupus erythematosus (SLE). As the CARD15 risk alleles had previously been assessed in our collection of 496 MS trios, we focused our efforts on the DLG5 risk allele and the IBD5(risk) haplotype (IBD5(risk)) for MS. While there is no evidence of association within our MS sample with either of these polymorphisms, screening of 1027 subjects with SLE suggests that IBD5(risk) may have a modest contribution to disease risk in the subset of SLE subjects without lupus nephritis. In addition, a pooled analysis of existing published and unpublished data in 1305 cases of SLE genotyped for the CARD15 risk alleles suggests that only the CARD15(908R) IBD risk allele may have a strong effect on risk of SLE. Our data, therefore, suggest that both the CARD15 gene and the IBD5 locus may have a role as general susceptibility loci for certain common, genetically complex inflammatory diseases.
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Affiliation(s)
- P L De Jager
- Center for Neurologic Diseases, Department of Neurology, Harvard Medical School and Brigham and Women's Hospital, MA, USA
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Lammers KM, Ouburg S, Morré SA, Crusius JBA, Gionchett P, Rizzello F, Morselli C, Caramelli E, Conte R, Poggioli G, Campieri M, Peña AS. Combined carriership of TLR9-1237C and CD14-260T alleles enhances the risk of developing chronic relapsing pouchitis. World J Gastroenterol 2006; 11:7323-9. [PMID: 16437636 PMCID: PMC4725145 DOI: 10.3748/wjg.v11.i46.7323] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the single nucleotide polymorphisms (SNPs) in genes involved in bacterial recognition and the susceptibility to pouchitis or pouchitis severity. METHODS Analyses of CD14 -260C>T, CARD15/NOD2 3020insC, Toll-like receptor (TLR)4 +896A>G, TLR9 -1237T>C, TLR9+2848G>A, and IRAKM + 22148G>A SNPs were performed in 157 ileal-pouch anal anastomosis (IPAA) patients (79 patients who did not develop pouchitis, 43 infrequent pouchitis patients, 35 chronic relapsing pouchitis patients) and 224 Italian Caucasian healthy controls. RESULTS No significant differences were found in SNP frequencies between controls and IPAA patients. However, a significant difference in carriership frequency of the TLR9-1237C allele was found between the infrequent pouchitis and chronic relapsing pouchitis groups [P = 0.028, oddos ratio (OR) = 3.2, 95%CI = 1.2-8.6]. This allele uniquely represented a 4-locus TLR9 haplotype comprising both studied TLR9 SNPs in Caucasians. Carrier trait analysis revealed an enhanced combined carriership of the alleles TLR9 -1237C and CD14 -260T in the chronic relapsing pouchitis and infrequent pouchitis group (P = 0.018, OR = 4.1, 95%CI = 1.4 -12.3). CONCLUSION There is no evidence that the SNPs predispose to the need for IPAA surgery. The significant increase of the combined carriership of the CD14 -260T and TLR9 -1237C alleles in the chronic relapsing pouchitis group suggests that these markers identify a subgroup of IPAA patients with a risk of developing chronic or refractory pouchitis.
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Affiliation(s)
- K M Lammers
- Department Internal Medicine and Gastroenterology, Policlinic S. Orsola, University of Bologna, Nuove patologie-Pad. 5, Via Massarenti 9, 40138 Bologna, Italy.
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Abstract
Over the past several years, significant advances have been made in the diagnostic techniques used in the management of ulcerative colitis and Crohn's disease. These advances have occurred mainly in the area of gastrointestinal endoscopy and radiology. Capsule endoscopy and double-balloon endoscopy have permitted better visualization of the small bowel mucosa. Advanced imaging techniques, including chromoendoscopy, magnification endoscopy, confocal endomicroscopy, and spectroscopy, may aid in the diagnosis of colorectal neoplasia in patients with long-standing disease. Improved radiographic imaging techniques based on computed tomography and magnetic resonance imaging allow noninvasive means of evaluating the small bowel in patients with known or suspected Crohn's disease. Finally, positron emission tomography is an investigative tool for inflammatory bowel disease that may also aid in the detection of inflammation in these diseases.
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Affiliation(s)
- Jonathan A Leighton
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, 13400 E. Shea Boulevard, Scottsdale, AZ 85259, USA.
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Abstract
There is a need for better endoscopic visualization in specific circumstances like detection of flat colorectal lesions and dysplasia-screening in ulcerative colitis. Chromoendoscopy is a technique with proven success, but many more, novel endoscopic techniques are currently under investigation. In this article different point measurement and still imaging methods are discussed: Raman spectroscopy, elastic (light) scattering spectroscopy, fluorescence spectroscopy, optical coherence tomography and confocal laser microscopy. Furthermore, real-time endoscopic imaging methods are discussed. These include narrow band imaging, fluorescence imaging and endocytoscopy. The results of fluoroscence imaging might be improved by application of photosensitizers or coupling of fluorescent dyes to tumour-related antigens (immunoscopy). Most of these techniques still have to be developed further and are not yet available for routine use. In our opinion, a combination of a red-flag technique and a microscopic technique carries an enormous potential.
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Affiliation(s)
- Evelien Dekker
- Department of Gastroenterology & Hepatology, Academic Medical Centre, Amsterdam, The Netherlands.
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Papaconstantinou I, Theodoropoulos G, Gazouli M, Panoussopoulos D, Mantzaris GJ, Felekouras E, Bramis J. Association between mutations in the CARD15/NOD2 gene and colorectal cancer in a Greek population. Int J Cancer 2005; 114:433-5. [PMID: 15578724 DOI: 10.1002/ijc.20747] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epidemiological observations suggest that cancer arises from chronically inflamed tissues. Inflammatory bowel disease (IBD) is a typical example since patients with longstanding IBD are at increased risk for development of colorectal cancer (CRC). Therefore, genetic factors predisposing to or implicated in the chronic inflammatory process in IBD may simultaneously predispose to CRC. Recently CARD15/NOD2 has been associated with IBD, which further strengthens the notion that the inflammatory response plays a crucial role in this disease. Several mutations have been identified in the CARD15/NOD2 gene, which appear with significantly higher frequency in patients with IBD. In this report, we have examined the frequency of the 3 major mutations R702W, G908R and 3020insC of the CARD2/NOD2 gene in a series of 104 consecutive Greek patients with sporadic colorectal cancer and 100 healthy individuals. The frequency of all the mutations was significantly elevated compared to the control population (R702W, OR=5.00, p=0.023; G908R, OR=2.78, p=0.025; 3020insC, OR=2.44, p=0.017). Patients with advanced stage tumors were more frequently carriers of at least 1 variant in the CARD15/NOD2 gene (p=0.009). Our results suggest that CARD2/NOD2 may be a genetic factor that predispose to sporadic colorectal cancer.
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20
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Gazouli M, Mantzaris G, Kotsinas A, Zacharatos P, Papalambros E, Archimandritis A, Ikonomopoulos J, Gorgoulis VG. Association between polymorphisms in the Toll-like receptor 4, CD14, and CARD15/NOD2 and inflammatory bowel disease in the Greek population. World J Gastroenterol 2005; 11:681-5. [PMID: 15655821 PMCID: PMC4250738 DOI: 10.3748/wjg.v11.i5.681] [Citation(s) in RCA: 138] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Crohn’s disease (CD) and ulcerative colitis (UC) are multifactorial diseases with a significant genetic background. Apart from CARD15/NOD2 gene, evidence is accumulating that molecules related to the innate immune response such as CD14 or Toll-like receptor 4 (TLR4), are involved in their pathogenesis. In further exploring the genetic background of these diseases, we investigated the variations in the CARD15/NOD2 gene (Arg702Trp, Gly908Arg and Leu1007fsinsC), and polymorphisms in the TLR4 gene (Asp299Gly and Thr399Ile) as well as in the promoter of the CD14 gene (T/C at position -159) in Greek patients with CD and UC.
METHODS: DNA was obtained from 120 patients with CD, 85 with UC and 100 healthy individuals. Genotyping was performed by allele specific PCR or by PCR-RFLP analysis.
RESULTS: The 299Gly allele frequency of the TLR4 gene and the T allele and TT genotype frequencies of the CD14 promoter were significantly higher in CD patients only compared to healthy individuals (P = 0.026<0.05; P = 0.0048<0.01 and P = 0.047<0.05 respectively). Concerning the NOD2/CARD15 mutations the overall presence in CD patients was significantly higher than that in UC patients or in controls. Additionally, 51.67% of the CD patients were carriers of a TLR4 and/or CD14 polymorphic allele and at least one variant of the NOD2/CARD15, compared to 27% of the UC patients. It should be pointed out that both frequencies significantly increased as compared with the 10% frequency of multiple carriers found in healthy controls. A possible interaction of the NOD2/CARD15 with TLR4 and especially CD14, increased the risk of developing inflammatory bowel disease (IBD).
CONCLUSION: Our results indicate that co-existence of a mutation in either the TLR4 or CD14 gene, and in NOD2/CARD15 is associated with an increased susceptibility to developing CD compared to UC, and to developing either CD or UC compared to healthy individuals.
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Affiliation(s)
- Maria Gazouli
- Department of Histology-Embryology, 53 Antaiou St. Ano Patisia, 11146 Athens, Greece
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21
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Annese V, Lombardi G, Perri F, D'Incà R, Ardizzone S, Riegler G, Giaccari S, Vecchi M, Castiglione F, Gionchetti P, Cocchiara E, Vigneri S, Latiano A, Palmieri O, Andriulli A. Variants of CARD15 are associated with an aggressive clinical course of Crohn's disease--an IG-IBD study. Am J Gastroenterol 2005; 100:84-92. [PMID: 15654786 DOI: 10.1111/j.1572-0241.2005.40705.x] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Three major variants of the CARD15 gene confer susceptibility to Crohn's disease (CD). Whether or not these variants correlate with specific clinical features of the disease is under evaluation. AIM We investigated the possible association of CARD15 variants with specific clinical characteristics, including the occurrence of anti-Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA), in a large cohort of inflammatory bowel disease (IBD) patients and their unaffected relatives. METHODS Three hundred and sixteen CD patients (156 with positive family history), 408 ulcerative colitis (UC) patients (206 with positive family history), 588 unaffected relatives, and 205 unrelated healthy controls (HC) were studied. Single nucleotide polymorphisms (SNPs) R702W, G908R, and L1007finsC of the CARD15 gene were investigated and correlated to age at diagnosis, gender, family history, localization, extraintestinal manifestations, previous resective surgery, stenosing/fistulizing pattern, ANCA, and ASCA. RESULTS Compared to HC, the frequencies of all three variants in CD were significantly increased: 8.7% versus 4.1% for R702W (p < 0.006), 7.3% versus 2.7% for G908R (p < 0.002), 9.3% versus 0.7% for L1007finsC (p < 0.00001). At least one risk allele was found in 38.2% (p < 0.0001, compared to HC), 13.7% (NS), and 15.1% of CD, UC, and HC, respectively. The L1007finsC risk allele was also significantly increased in unaffected relatives of familial (9.5%; p < 0.00001), and sporadic CD (9%; p < 0.00001), compared to HC (0.7%). Sixteen healthy relatives, carriers of two risk alleles, were asymptomatic after 5-8 yr of follow-up. CD carriers of at least one variant were younger (p= 0.03), more likely to have ileal localization (p= 0.0001), stenosing pattern (p= 0.01), previous resective surgery (p= 0.0001), and presence of ASCA (p= 0.0001). No difference in SNPs frequency between familial and sporadic cases of CD was found. CONCLUSION In our population, both familial and sporadic CD patients carrying at least one major variant of CARD15 had an aggressive clinical course.
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Affiliation(s)
- Vito Annese
- Gastroenterology Unit, CSS-IRCCS Hospital, Viale Cappuccini 1, 71013 San Giovanni Rotondo, Italy
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22
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Gazouli M, Zacharatos P, Mantzaris GJ, Barbatis C, Ikonomopoulos I, Archimandritis AJ, Lukas JC, Papalambros E, Gorgoulis V. Association of NOD2/CARD15 variants with Crohn's disease in a Greek population. Eur J Gastroenterol Hepatol 2004; 16:1177-82. [PMID: 15489579 DOI: 10.1097/00042737-200411000-00016] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Single nucleotide polymorphisms in the NOD2/CARD15 gene have recently been shown to be associated with Crohn's disease (CD), but whether this susceptibility extends to all ethnic groups and geographic areas remains unknown. The aim of the present study was to evaluate the NOD2/CARD15 mutations in Greek patients with CD. METHODS Individuals were genotyped for three NOD2/CARD15 mutations: R702W, G908R and L1007fsinsC. Blood samples were obtained from 120 patients with CD, 85 patients with ulcerative colitis, and 100 unrelated healthy controls. RESULTS Mutations in NOD2/CARD15 were observed with significantly greater frequency in CD patients (98/120, 81.7%) than in ulcerative colitis patients (40/85, 47%) (P < 0.0001) or in healthy individuals (21/100, 21%) (P < 0.0001). For CD patients, compared with controls, the odds were increased for carriage of the R702W (odds ratio, 12.25) and less for the G908R (odds ratio, 5.2) and L1007fsinsC (odds ratio, 3.9) mutations. The age of onset of CD was lower in Greek mutation carriers as compared with non-carriers of Greek origin (28.2 +/- 14.6 years versus 34 +/- 12.3 years, respectively; P = 0.036). Additionally, the frequency of NOD2/CARD15 mutations was increased in ileitis or ileocolitis compared with non-ileal disease. CONCLUSIONS The NOD2/CARD15 mutations are risk factors for CD in Greece, they appear to predict an earlier age of onset and are associated particularly with ileitis or ileocolitis.
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Affiliation(s)
- Maria Gazouli
- Department of Histology-Embryology (Molecular Carcinogenesis Group), Medical School, University of Athens, Greece
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Hollenbach E, Neumann M, Vieth M, Roessner A, Malfertheiner P, Naumann M. Inhibition of p38 MAP kinase- and RICK/NF-kappaB-signaling suppresses inflammatory bowel disease. FASEB J 2004; 18:1550-2. [PMID: 15289440 DOI: 10.1096/fj.04-1642fje] [Citation(s) in RCA: 188] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ulcerative colitis and Crohn's disease are the two entities of chronic inflammatory bowel diseases (IBD). One of the main pathogenic mechanisms is probably a dysregulated immune response triggered by products of the enteric bacterial flora. The goal of this study was to evaluate the effects of the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 on inflammatory responses using the DSS-induced experimental colitis model in mice reflecting human IBD. We found that SB203580 improved the clinical score, ameliorates the histological alterations, and reduces the mRNA levels of proinflammatory cytokines. In addition to p38 kinase activity, the "classical" and the "alternative" NF-kappaB pathways were also strongly activated during colitis induction. All three pathways were drastically down-regulated by SB203580 treatment. An analysis of the molecular basis of NF-kappaB activation revealed that Rip-like interacting caspase-like apoptosis-regulatory protein kinase (RICK), a key component of a pathway leading to NF-kappaB induction, is also strongly inhibited by SB203580. Since RICK is an effector kinase of NOD2, an intracellular receptor of bacterial peptidoglycan, these results support the notion that NOD signaling could play a pivotal role in the IBD pathogenesis. Thus, RICK could represent a novel target for future therapies in human IBD.
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Affiliation(s)
- Eike Hollenbach
- Institute of Experimental Internal Medicine, Otto-von-Guericke-University, Magdeburg, Germany
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